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1.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

3.
Orphanet J Rare Dis ; 13(Suppl 1): 7, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29799382

RESUMO

BACKGROUND: The two pediatric cystic fibrosis centers (CFCs) in Paris (Robert Debré) and Nantes, France, have been developing therapeutic patient education (TPE) programs since 2006 and have been engaged in the pilot phase of the quality improvement program (QIP) named the Hospital Program to Improve Outcomes and Expertise in Cystic Fibrosis (PHARE-M) since 2011. The objective was to improve the FEV1 of the cohort of adolescents to prepare them for their optimal transition to an adult CFC. METHODS: The two CFCs formed a multidisciplinary quality team and used the analysis of causes of insufficient respiratory function taking into account the adolescents' psychosocial factors. At the Nantes CFC, the approach was centered on adolescents' body image and their motivation to take care of themselves by assigning specific aspects of patient follow-up to each professional in the team. At R. Debré, an individual cause-and-effect diagram identified for each patient the medical and psychosocial factors that could account for insufficient respiratory function. Personalized actions were offered to each patient. RESULTS: In 2014, the median FEV1 (Forced Expiratory Volume in 1 Second) of the adolescent cohort exceeds 90% at the 2 CFCs (Nantes and R. Debré). Between 2011 and 2014 both centers improved their ranking for FEV1% in adolescents in the Registry histograms. At R. Debré, the personalized process allowed to reinforce equality of care, offering to all the opportunity to benefit from TPE sessions and coaching with an adapted physical activity teacher. The psychologist developed a specific tool to support the patient-centered process. CONCLUSION: The link between TPE and QIP was strong at our two centers enhancing patient centered care and targeting an optimal transition to an adult program.

4.
BMJ Paediatr Open ; 1(1): e000089, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29637125

RESUMO

Introduction: As the most recent French bronchiolitis guidelines were published in 2000, there is a current overinvestigation and an overtreatment of infants hospitalised with bronchiolitis in France. In 2012, the Group of Pediatric University Hospitals in Western France ('HUGO') proposed new evidence-based clinical practice guidelines in keeping with the latest international guidelines. We hypothesise that the implementation of these guidelines contributed to the quality improvement of the management of bronchiolitis in our hospital. The aim of this study was to determine the impact of these guidelines on the management of bronchiolitis inpatients. Methods: This retrospective before/after study design was conducted in the general paediatric unit of a tertiary care French hospital, looking at 1 year before (ie, the winter of 2011-2012) and 1 year after (ie, the winter of 2013-2014) the implementation of the guidelines. Two hundred and eighty bronchiolitis inpatients, all less than 1 year of age, 115 in 2011-2012 and 165 in 2013-2014, were included. The primary outcome we sought to evaluate was the proportion of children administered a diagnostic test associated with a treatment not routinely recommended by the guidelines. As balancing measures, we evaluated the length of stay, the intensive care unit transfer and the readmission rates. Results: Following implementation of the guidelines, use of any given treatment associated with a diagnostic test was reduced by 66% (p<0.001). There were major decreases in the use of chest X-ray (86%vs26%, p<0.001), antibiotics (38%vs13%, p<0.001) and corticosteroids (10%vs3%, p=0.011). Balancing measures were not significantly different. Conclusions: HUGO guidelines were effective at reducing the administration of unnecessary diagnostic tests and medications. This study was the first step in convincing French paediatricians to streamline their practices until updated national guidelines are published.

5.
J Agric Food Chem ; 63(28): 6475-83, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-26172436

RESUMO

Epidemiological data suggest a link between food allergies and the subsequent development of asthma. Although this progression may result from the additional effects of exposure to multiple allergens, whether both allergies amplify each other's effects remains unknown. This study investigated whether oral exposure to food allergens influences the outcomes of subsequent respiratory exposure to an asthma-inducing allergen. Mice were sensitized and orally challenged with wheat (FA) and then exposed to house dust mite (HDM) extract (RA). Immunoglobulin (Ig), histamine, and cytokine levels were assayed by ELISA. Intestinal and lung physiology was assessed. Ig levels, histamine release, and cytokine secretion were higher after exposure to both allergens than after separate exposure to each. Intestinal permeability was higher, although airway hyper-responsiveness and lung inflammation remained unchanged. Exposure to food and respiratory allergens amplifies systemic and gut allergy-related immune responses without any additional effect on lung function and inflammation.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/imunologia , Animais , Proliferação de Células , Citocinas/metabolismo , Histamina/sangue , Imunoglobulinas/sangue , Pulmão , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia , Sistema Respiratório/citologia , Sistema Respiratório/imunologia , Triticum/imunologia
6.
Rev Prat ; 65(5): 639-43, 2015 May.
Artigo em Francês | MEDLINE | ID: mdl-26165098

RESUMO

The management of children dyspnea depends on the severity and symptomatology. The severity assessment requires knowledge of the standards of respiratory rate by age and signs of failure ventilatory mechanics. Recognize the time of dyspnea is important because it guides the diagnosis. Inspiratory dyspnea is most often due to viral laryngitis but an age of less than 6 months or no vaccination against Haemophilus should suggest other urgent diagnostics. Dyspnea with inspiratory and expiratory wheeze is a sign of tracheal damage and needs specialized hospital care. Expiratory dyspnea is the sign of a lower airway affection. A first episode of wheezing during epidemics sign acute bronchiolitis whose support is purely symptomatic with DRP and nutritional splitting. Corticosteroids, bronchodilators and chest physiotherapy are not indicated. Asthma attack is defined as a third episode of wheezing, that requires the administration of salbutamol with an inhalation room, and even oral corticosteroids. Febrile dyspnea must seek auscultatory or radiological abnormalities confirming pneumonia to be treated by a probabilistic and emergency antibiotherapy.


Assuntos
Dispneia , Obstrução das Vias Respiratórias/diagnóstico , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/terapia , Criança , Pré-Escolar , Diagnóstico Diferencial , Dispneia/diagnóstico , Dispneia/terapia , Corpos Estranhos/diagnóstico , Corpos Estranhos/terapia , Hospitalização , Humanos , Lactente , Recém-Nascido
8.
Respir Res ; 15: 142, 2014 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-25433406

RESUMO

BACKGROUND: Atopic march refers to the typical transition from a food allergy in early childhood to allergic asthma in older children and adults. However the precise interplay of events involving gut, skin and pulmonary inflammation in this process is not completely understood. OBJECTIVES: To develop a mouse model of mixed food and respiratory allergy mimicking the atopic march and better understand the impact of food allergies on asthma. METHODS: Food allergy to ovalbumin (OVA) was induced through intra-peritoneal sensitization and intra-gastric challenge, and/or a respiratory allergy to house dust mite (HDM) was obtained through percutaneous sensitization and intra-nasal challenges with dermatophagoides farinae (Der f) extract. Digestive, respiratory and systemic parameters were analyzed. RESULTS: OVA-mediated gut allergy was associated with an increase in jejunum permeability, and a worsening of Der f-induced asthma with stronger airway hyperresponsiveness and pulmonary cell infiltration, notably eosinophils. There was overproduction of the pro-eosinophil chemokine RANTES in broncho-alveolar lavages associated with an enhanced Th2 cytokine secretion and increased total and Der f-specific IgE when the two allergies were present. Both AHR and lung inflammation increased after a second pulmonary challenge. CONCLUSION: Gut sensitization to OVA amplifies Der f-induced asthma in mice.


Assuntos
Antígenos de Dermatophagoides , Proteínas de Artrópodes , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Hipersensibilidade Alimentar/imunologia , Intestinos/imunologia , Pulmão/imunologia , Ovalbumina , Animais , Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstrição , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/metabolismo , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Mucosa Intestinal/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Camundongos Endogâmicos BALB C , Permeabilidade , Pneumonia/imunologia , Pneumonia/metabolismo , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Tempo
9.
PLoS One ; 9(1): e85976, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24497934

RESUMO

BACKGROUND: Allergic asthma is caused by abnormal immunoreactivity against allergens such as house dust mites among which Dermatophagoides farinae (Der f) is a common species. Currently, immunotherapy is based on allergen administration, which has variable effect from patient to patient and may cause serious side effects, principally the sustained risk of anaphylaxis. DNA vaccination is a promising approach by triggering a specific immune response with reduced allergenicity. OBJECTIVE: The aim of the study is to evaluate the effects of DNA immunization with Der f1 allergen specific DNA on allergic sensitization, inflammation and respiratory function in mice. METHODS: Mice were vaccinated 28 and 7 days before allergen exposure with a Der f1-encoding plasmid formulated with a block copolymer. Asthma was induced by skin sensitization followed by intra-nasal challenges with Der f extract. Total lung, broncho-alveolar lavage (BAL) and spleen cells were analyzed by flow cytometry for their surface antigen and cytokine expression. Splenocytes and lung cell IFN-γ production by CD8+ cells in response to Der f CMH1-restricted peptides was assessed by ELISPOT. IgE, IgG1 and IgG2a were measured in serum by ELISA. Specific bronchial hyperresponsiveness was assessed by direct resistance measurements. RESULTS: Compared to animals vaccinated with an irrelevant plasmid, pVAX-Der f1 vaccination induced an increase of B cells in BAL, and an elevation of IL-10 and IFN-γ but also of IL-4, IL-13 and IL-17 producing CD4+ lymphocytes in lungs and of IL-4 and IL-5 in spleen. In response to CD8-restricted peptides an increase of IFN-γ was observed among lung cells. IgG2a levels non-specifically increased following block copolymer/DNA vaccination although IgE, IgG1 levels and airways resistances were not impacted. CONCLUSIONS & CLINICAL RELEVANCE: DNA vaccination using a plasmid coding for Der f1 formulated with the block copolymer 704 induces a specific immune response in the model of asthma used herein.


Assuntos
Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Asma/imunologia , Cisteína Endopeptidases/imunologia , Modelos Animais de Doenças , Pyroglyphidae/imunologia , Vacinas de DNA/imunologia , Administração Intranasal , Animais , Antígenos de Dermatophagoides/genética , Proteínas de Artrópodes/genética , Asma/prevenção & controle , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cisteína Endopeptidases/genética , Citocinas/imunologia , Citocinas/metabolismo , ELISPOT , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Polímeros/química , Pyroglyphidae/genética , Pele/imunologia , Baço/imunologia , Baço/metabolismo , Baço/patologia , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Vacinas de DNA/química
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